Healing Haze?

MEDICAL MARIJUANA poses dilemmas for politicians, but scientists see tremendous therapuetic promise in the drug's derivatives and synthetic forms.

The U.S. Supreme Court's recent decision against California¿s cannabis clubs has revived arguments over the legal use of marijuana for medicinal purposes. But no matter what the politics, researchers are continuing to develop synthetics of the drug that can be taken as a pill or absorbed through a patch. For the past 15 years Marinol¿a synthetic pill made by Unimed Pharmaceuticals¿has been the only available (and legal) alternative to marijuana. But soon Marinol, which has received mixed reviews, will not be alone on the shelf.

In fact, humans have smoked marijuana for thousands of years; the plant was given as medicine in the United States until the early 1900s and did not become a controlled substance until 1934. Marijuana remains a Schedule 1 substance today along with the likes of heroin, although Marinol was recently "declassified" to a Schedule 3 drug, which has looser prescription requirements.

Scientists in both academia and the pharmaceutical industry have tested marijuana derivatives and synthetic forms of the herb for potentially helpful chemical effects since the 1970s. But the idea that drugs based on marijuana could benefit people gained real support only recently. In 1990 Lisa Matsuda cloned CB1, the first cannabinoid receptor discovered in rats, and Shawn Munro cloned a second receptor (CB2 in humans) in 1993. From these studies, scientists came to discover that mammals have their own built-in cannabinoid molecules (endogenous or endo-cannabinoids).

Indeed, our bodies use endo-cannabinoids in much the same way as they use opioids in the central nervous system: as synapse agonists and antagonists. Christian Felder, who once worked with Matsuda at the National Institutes of Health and now works for Eli Lilly, describes a synapse as a gap in a line of connections in the brain. He likens the neurotransmitters released across the gap to bridges. The gaps help to regulate signaling in the brain, and the bridges are the "connection across a synapse [that] is the release key that fits into a very specific lock to initiate the next step."

An agonist is a key that fits in a lock and allows it to open. In contrast, an antagonist will fit into the lock but doesn¿t open it. "It blocks that binding site," Felder explains. "The beauty of that system is that you create an antagonist and that will sit there like a block; it won¿t let the agonist in." Delta9¿tetrahydrocannabinol, or THC, one of the main active ingredients in marijuana¿is an agonist, for instance. Given to an AIDS patient or cancer patient, who may be losing weight dramatically, Felder says, "it stimulates their appetite."

NATURAL VERSUS SYNTHETIC. THC (top) is one of marijuana's most active components. But CP55, 940 (bottom), a synthetic, is far more potent because it is designed to fit tightly into the receptor, allowing it to stay active longer.

The main difference between endogenous cannabinoids and opioids, Felder explains, is that cannabinoids are part of the fat family, which also distinguishes them from other neurotransmitters. As fats they cannot be stored, like other neurotransmitters, in packages called vesicles; they need "middlemen" to relay messages from one cell to another. So far, about half a dozen endogenous cannabinoids have been identified, but these molecules are not as useful to drug developers as the rigidly structured lipophilic (or fat-loving) forms in marijuana. The plant itself contains some 400 cannabinoids, each of which may have some therapeutic potential. How to use them in a way that allows the body to reap the greatest benefit, however, is up for debate.